Abstract On average, >90% of patients who suffer from a cardiac arrest die. Nearly all die unexpectedly from this leading cause of death, in part, because the essential components of standard CPR (S-CPR): manual chest compressions at a rate of 100/min, 1 to 1.5 inches in depth and positive pressure ventilations, are an inherently inefficient process, providing less than 25% of normal blood flow to the heart and brain. Despite intensive research, little or no improvement in outcomes has been observed for over half a century. This application builds upon our new understanding of ways to optimize blood flow to the heart and brain during CPR and protect these organs from reperfusion injury. It promises to provide new hope for patients who suffer from sudden cardiac death. The proposed research is focused on demonstrating proof of concept that reducing or preventing reperfusion injury by utilizing a bolus dose of anesthetic during the initiation of CPR is both feasible and critical to markedly enhancing survival with favorable neurological function after cardiac arrest. Building upon recent and significant advances in the treatment of cerebral and cardiac ischemia, where controlled reperfusion has been shown to strikingly reduce stroke and infarct size in patients with cerebral vascular events and myocardial infarction, we have recently administered a bolus dose of sevoflurane during the first three minutes of CPR in a pig model of prolonged untreated cardiac arrest. The results have been striking: after 15 minutes of untreated ventricular fibrillation, performing CPR with a bolus dose of sevoflurane during the first three minutes of circulation in conjunction with a means to optimize blood flow to the heart and brain during CPR has normalized brain and heart function < 24-hours after arrest. These exciting observations contradict what was previously thought impossible; to restore full life in the setting of prolonged absence of flow and severe metabolic derangement. This novel approach that significantly reduces and in some cases prevents reperfusion injury may result in a novel and clinically important method of CPR that is easy to implement by EMS personnel and in the home. It provides the promise, based upon sound physiological principles and concepts, to markedly improve neurologically intact survival in patients that have heretofore never been possible to resuscitate. In this application we propose to further explore these findings. In the current application we propose to a) demonstrate preclinical proof-of-concept that early administration of inhaled anesthetic for reperfusion injury protection will result in superior hemodynamics and survival with favorable neurological outcomes in established animal models of prolonged (15 minutes) ventricular fibrillation cardiac arrest with and without bystander CPR and pulseless electrical activity, and b) design a device capable of administering a bolus dose of sevoflurane to provide a means to provide protection from reperfusion injury available to EMS BLS providers. If successful, this therapy will result in saving >10,000 more Americans each year from out of hospital cardiac arrest and a similar number of in-hospital survivors based upon the superior blood flow and the ability afforded by PC to protect the brain and heart from reperfusion injury during CPR.